Candida species are among the most common causes of hospital-acquired infections. Candidiasis is associated with substantial mortality, morbidity, and high hospitalization costs. Ongoing problems with antifungal efficacy and resistance make the development of novel immunotherapeutic approaches highly attractive. Such approaches include a Candida vaccine and passive immunotherapy with anti-Candida antibodies. We have discovered that the Candida albicans protein, agglutinin-like sequence-1 (Als1p) is a potent adhesin for human vascular endothelial cells. We have also found that four additional members of the Als protein family mediate attachment to distinct profiles of host substrates including fibronectin, gelatin, epithelial cells and endothelial cells. Our initial experiments have shown that immunization with recombinant Als1p, and antibodies to the N-terminus of the protein protect mice against lethal challenge of intravenous C. albicans. Therefore, the Als protein family provides promising targets immunotherapeutic strategies. In our proposed experiments, we will 1) define the precise domains of Als proteins that mediate substrate specific binding; 2) determine the three-dimensional structure of these binding domains; 3) identify the endothelial cell ligands which are bound by Als proteins, and 4) determine the in vivo expression profiles of ALS genes, and the tissue tropism they confer. Accomplishing these goals will advance the basic understanding of C. albicans interactions with the host at the receptor-ligand level. The results of these studies will enable our future development of novel immunotherapeutic approaches to block candidal adherence and enhance host defense.